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Conventional approaches to address these issues involve the synthesis of lipid\u2010prodrug by incorporating responsive covalent linkers. However, such approaches often result in suboptimal sensitivity for drug release and undermine therapeutic effectiveness. Herein, the study reports a fundamentally different concept for designing lipid\u2010like prodrugs through boron\u2013nitrogen (B\u2010N) coordination and dynamic covalent interaction. The 5\u2010fluorouracil\u2010based lipid\u2010like prodrugs, featuring a borate ester consisting of a glycerophosphoryl choline head and a boronic acid\u2010modified 5Fu\/dodecanamine complex tail, are used to prepare pH\/H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub> cascade\u2010responsive LNPs (5Fu\u2010LNPs). The 5Fu\u2010LNPs exhibit enhanced DLC and stability in a neutral physiological environment due to the B\u2010N coordination and enhanced hydrophobicity. In tumors, acidic pH triggers the dissociation of B\u2010N coordination to release prodrugs, which further responds to low H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub> concentrations to release drugs, showcasing a potent pH\/H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub>\u2010cascade\u2010responsive property. Importantly, 5Fu\u2010LNPs demonstrate greater antitumor efficiency and lower toxicity compared to the commercial 5Fu. These results highlight 5Fu\u2010LNPs as a safer and more effective alternative to chemotherapy. This work presents a unique LNP fabrication strategy that can overcome the limitations of conventional LNPs and broaden the range of intelligent nanomaterial preparation techniques.<\/jats:p>","DOI":"10.1002\/smll.202308790","type":"journal-article","created":{"date-parts":[[2024,2,24]],"date-time":"2024-02-24T03:55:25Z","timestamp":1708746925000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["pH\/H<sub>2<\/sub>O<sub>2<\/sub> Cascade\u2010Responsive Nanoparticles of Lipid\u2010Like Prodrugs through Dynamic\u2010Covalent and Coordination Interactions for Chemotherapy"],"prefix":"10.1002","volume":"20","author":[{"given":"Wanyue","family":"Xiao","sequence":"first","affiliation":[{"name":"Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medica Hubei Engineering Research Center for Biomaterials and Medical Protective Materials School of Chemistry and Chemical Engineering Huazhong University of Science and 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